The Use of ATP-Release Identifies Platelet Function Disorders in Patients with Bleeding Disorder of Unknown Cause (BDUC) and Normal LTA Results

Background: About 60-70% of patients that are referred to a medical specialist with an increased bleeding tendency remain undiagnosed after extensive laboratory testing. These patients are classified as having a Bleeding Disorder of Unknown Cause (BDUC). The golden standard for the assessment of platelet function is light transmission aggregometry (LTA), but this technique is not able to detect all platelet granule defects. Therefore, the aim of this study was to investigate the additional diagnostic value of lumi-aggregomtery/ATP-release on top of LTA in patients with an increased bleeding tendency, to test for dense granule secretion disorders. Methods: Data from 336 patients in the ProBe-AHP study, including patients referred for analysis of an increased bleeding tendency, were used. The CHRONO-LOG® 490 4+4 light transmission aggregometer was used to perform LTA and the CHRONO-LOG® model 700 lumi- aggregometer was used to measure ATP-release by luminometry. LTA was performed according to the consensus SSC ISTH document by Cattaneo et al. For ATP-release, collagen, epinephrine and an thromboxane A2 analogue (U46619) were used as agonists. An abnormal LTA outcome was defined as more than one abnormal agonists and an abnormal ATP-release outcome was defined as one or more abnormal agonists. Other clinical and laboratory pre-existing data, including medical history, ISTH-BAT score and routine coagulation tests, were available. Results: In 274/336 patients LTA was performed and in 74/274 patients, additional ATP-release was done. LTA showed abnormal results in 41/274 (15%) of the patients and ATP-release showed abnormal results in 13/74 (18%) of the patients. Within the group of 74 patients in whom LTA and ATP-release was performed, initially 41 patients were diagnosed with BDUC, 15 patients with no bleeding disorder (NBD), 13 patients with a PFD (based on LTA), 1 patient with hyperfibrinolysis, 3 patients with von Willebrands disease type 1 and 1 patient with a mild FVII deficiency. After the performance of ATP-release, 10 additional diagnoses of PFD were made within the group of patients that were diagnosed with BDUC (n=10/41). This implicates a diagnostic yield of 24% with the use of additional ATP-release on top of LTA in this relatively small group of BDUC-patients. Conclusion: Our study showed that the addition of ATP-release testing to the diagnostic algorithm for patients with an increased bleeding tendency leads to more diagnoses of platelet function disorders, reducing the number of patients that are classified as having BDUC. Therefore, and in line with recommendations from previous studies, it is advised to perform platelet dense granule tests on top of LTA, if available, in patients with in an increased bleeding tendency.